title: A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity.
abstract: The epidermal growth factor receptor (EGFR) and the type I insulin-like growth factor receptor (IGF-1R) are two cell surface receptor tyrosine kinases known to cooperate to promote tumor progression and drug resistance. Combined blockade of EGFR and IGF-1R has shown improved anti-tumor activity in preclinical models. Here, we report the characterization of a stable IgG-like bispecific antibody (BsAb) dual-targeting EGFR and IGF-1R that was developed for cancer therapy. The BsAb molecule (EI-04), constructed with a stability-engineered single chain variable fragment (scFv) against IGF-1R attached to the carboxyl-terminus of an IgG against EGFR, displays favorable biophysical properties for biopharmaceutical development. Biochemically, EI-04 bound to human EGFR and IGF-1R with sub nanomolar affinity, co-engaged the two receptors simultaneously, and blocked the binding of their respective ligands with similar potency compared to the parental monoclonal antibodies (mAbs). In tumor cells, EI-04 effectively inhibited EGFR and IGF-1R phosphorylation, and concurrently blocked downstream AKT and ERK activation, resulting in greater inhibition of tumor cell growth and cell cycle progression than the single mAbs. EI-04, likely due to its tetravalent bispecific format, exhibited high avidity binding to BxPC3 tumor cells co-expressing EGFR and IGF-1R, and consequently improved potency at inhibiting IGF-driven cell growth over the mAb combination. Importantly, EI-04 demonstrated enhanced in vivo anti-tumor efficacy over the parental mAbs in two xenograft models, and even over the mAb combination in the BxPC3 model. Our data support the clinical investigation of EI-04 as a superior cancer therapeutic in treating EGFR and IGF-1R pathway responsive tumors.
authors.affiliation: Biogen Idec Oncology Discovery; San Diego, CA, USA. jianying_dong@yahoo.com
authors.forename: Jianying
authors.initials: J
authors.lastname: Dong
authors.forename: Arlene
authors.initials: A
authors.lastname: Sereno
authors.forename: Dikran
authors.initials: D
authors.lastname: Aivazian
authors.forename: Emma
authors.initials: E
authors.lastname: Langley
authors.forename: Brian R
authors.initials: BR
authors.lastname: Miller
authors.forename: William B
authors.initials: WB
authors.lastname: Snyder
authors.forename: Eric
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authors.lastname: Cantele
authors.forename: Ronald
authors.initials: R
authors.lastname: Morena
authors.forename: Ingrid B J K
authors.initials: IB
authors.lastname: Joseph
authors.forename: Antonio
authors.initials: A
authors.lastname: Boccia
authors.forename: Cyrus
authors.initials: C
authors.lastname: Virata
authors.forename: James
authors.initials: J
authors.lastname: Gamez
authors.forename: Grace
authors.initials: G
authors.lastname: Yco
authors.forename: Michael
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authors.lastname: Favis
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Wu
authors.forename: Christilyn P
authors.initials: CP
authors.lastname: Graff
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Ellen
authors.initials: E
authors.lastname: Rohde
authors.forename: Rachel
authors.initials: R
authors.lastname: Rennard
authors.forename: Lisa
authors.initials: L
authors.lastname: Berquist
authors.forename: Flora
authors.initials: F
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Gao
authors.forename: Steffan N
authors.initials: SN
authors.lastname: Ho
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Demarest
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Reff
authors.forename: Kandasamy
authors.initials: K
authors.lastname: Hariharan
authors.forename: Scott M
authors.initials: SM
authors.lastname: Glaser
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D000915:Antibody Affinity / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D015153:Blotting, Western; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D057127:Single-Chain Antibodies / Q000276:immunology / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D057127:Single-Chain Antibodies; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1